Nutritional interventions in prehabilitation for cancer surgery

Purpose of review Nutrition remains a key focus in the preoptimization of patients undergoing cancer surgery. Given the catabolic nature of cancer, coupled with the physiological insult of surgery, malnutrition (when assessed) is prevalent in a significant proportion of patients. Therefore, robust research on interventions to attenuate the detrimental impact of this is crucial. Recent findings As a unimodal prehabilitation intervention, assessment for malnutrition is the first step, as universal supplementation has not been shown to have a significant impact on outcomes. However, targeted nutritional therapy, whether that is enteral or parenteral, has been shown to improve the nutritional state of patients’ presurgery, potentially reducing the rate of postoperative complications such as nosocomial infections. As part of multimodal prehabilitation, the situation is more nuanced given the difficulty in attribution of effects to the differing components, and vast heterogeneity in intervention and patient profiles. Summary Multimodal prehabilitation is proven to improve length of hospital stay and postoperative outcomes, with nutrition forming a significant part of the therapy given. Further work is required to look at not only the interplay between the optimization of nutritional status and other prehabilitation interventions, but also how to best select which patients will achieve significant benefit.


AN INTRODUCTION TO NUTRITIONAL PREHABILITATION IN CANCER CARE
Cancer prehabilitation is a process on the continuum of care that occurs between the time of cancer diagnosis and the beginning of acute treatment (i.e., surgical resection). This is often based around the identification of impairments, which may be physical and/or psychological, and the subsequent delivery of targeted interventions to improve a patient's 'resilience' to treatment. There is a growing body of evidence to support the notion that cancer prehabilitation can reduce both the incidence and severity of current and future clinical insults [1]. Specific to nutritional prehabilitation, patients with cancer often face nutritional challenges, with up to 80% of patients with cancer found to have varying degrees of malnutrition [2 && ], largely attributed to inflammatory mediators released in response to tumor cells [3]. As such, optimization of nutritional status and associated physiological parameters is often a key target of prehabilitation regimes. This review serves to highlight current evidence in the field of nutritional prehabilitation for cancer surgery, both as an independent strategy and as part of multimodal interventions. nutritional impact on patients at the time of presentation due to symptoms such as dysphagia, which coupled with a tendency towards a later staging at diagnosis, can seriously hinder attempts to achieve a curative outcome [4]. In these cancer types in particular, but also in others such as pancreatic cancer or patients undergoing neoadjuvant treatment [5,6], both nutritional screening, subsequent assessment of at-risk patients, then intervention, is key to being able to improve morbidity, mortality and psychological outcomes in patients undergoing oncological resections [7]. In support of this, evidence from Gillis and colleagues used pooled data from five prehabilitation studies to demonstrate that in patients with colorectal cancer, those with malnutrition suffer poor physical and mental health before elective resection [8].
Numerous studies have looked at various methods of screening to identify patients at risk of malnutrition prior to cancer surgery, with a commonly stated aim of facilitating appropriate nutritional intervention. Despite this, a universal recommendation, either within or across cancer types, on how best to screen patients with cancer has not been reached. A recent systematic review by Deftereos et al. [9], focusing on gastrointestinal (GI) cancers, suggested that recommendations regarding the use of one screening tool over another could not be made, but that screening tools well validated in general clinical populations, and if possible other oncology populations, should be used.
Despite a relative wealth of literature on nutritional screening and assessment tools, fewer studies have looked at the impact of nutritional interventions alone to attenuate the known risks associated with poor nutritional status such as poor wound healing and infectious complications. Further, the varying effects of different cancers on often heterogeneous cohorts of patients make the formulation of overarching guidelines that apply to all scenarios extremely difficult to achieve. As such, those studies that do exist often focus on the groups of patients in whom malnutrition is most prevalent and/or impactful, such as those highlighted above. However, even in these high-risk groups limited evidence exists. Cantwell et al. [10] performed a systematic review of nutritional prehabilitation (excluding parenteral nutrition) in head and neck cancer, and found not only a low yield of eligible studies (n ¼ 2) but also no significant improvements in surgical outcomes or physical function.
Oral nutritional supplementation (ONS) is a widely used method to add nutrients in patients atrisk of malnutrition or who are under nourished and not achieving their target dietary intake. However, the impact of its use in the preoperative period and whether it should be used selectively or in all patients with cancer undergoing surgery is still debated. A systematic review by Reece and colleagues exploring the impact of ONS for patients undergoing surgery for GI cancer reported limited evidence for the use of ONS to increase dietary intake or positively influence body weight. They did however conclude that this was likely due to populations, interventions, outcomes and follow-up timeframes each being variable across studies, and that further research into optimal interventions and their timing is needed [11]. Further, with regards to the possibility of preoperative ONS improving postoperative feeding tolerance, He et al. [12] randomized 67 patients undergoing subtotal or total gastrectomy to preoperative ONS or dietary advice alone. They found that preoperative ONS did not improve the incidence of GI intolerance, and there was no significant difference in postoperative complication rates between the two groups.
Clearly for any nutritional intervention to have a positive impact, feasibility in terms of delivery and uptake/compliance is key. With regards to the delivery and uptake (i.e., whether patients engage and consume them) of ONS there is evidence to support its ease in delivery to patients. In a singlesite randomized trial, Serrano et al. [13] conducted a feasibility trial comparing ONS with placebo. Providing 30-days of preoperative ONS which continued for 5 days after surgery, no significant differences in the rate of postoperative complications were reported, although a slightly higher rate of infectious complications in the placebo group was observed. Importantly for a feasibility study, the overall compliance rate was high at 80%. Deftereos et al. [14 ] underwent a mixed-methods multicenter study to analyze the implementation of a standardized nutrition care pathway in patients with upper GI cancer undergoing surgery. They used a validated theoretical framework

KEY POINTS
Nutritional prehabilitation should be considered after assessing for malnutrition and if possible, enteral options should be considered primarily.
High risk patients are most likely to benefit from nutritional prehabilitation.
Nutritional care pathways are an effective intervention to identify and intervene with expert dietetic input, but these require significant resource and stake holder involvement.
It is likely that nutritional interventions as part of multimodal prehabilitation will yield the most effective results.
for implementation and performed surveys and interviews the staff involved. Patients were highly appreciative of the service, which included a dietetic-led structured and standardized preoperative outpatient service, and dieticians found there to be more proactive engagement with nutritional support. However, the main barriers were the need for significant funding to enable a dietician-led care pathway as well as integrating the service to the existing pathways, suggestive that a 'one-size fits all' approach may not be optimal in creating a successful nutritional prehabilitation service.
One emerging trial which may be able to determine whether ONS does impact postoperative complications is the PeriNutri trial. A prospective, multicenter randomized controlled trial, PeriNutri will explore if perioperative ONS in patients with colon cancer undergoing resectional surgery decreases the rate of postoperative 30-day morbidity, and also includes a 5-year follow-up for diseasefree and overall survival [15]. This trial offers the possibility of a high-quality study to explore the impact of ONS on both short-and long-term postoperative morbidity in patients with colorectal cancer, although the conclusion may need to be slightly more nuanced when adjusting for other factors such as immediate postoperative complications (i.e., ileus) that may impact the ability of patients to adequately absorb ONS in the inpatient period. Further, given the gold-standard for colorectal surgery management in the elective setting is enhanced recovery after surgery (ERAS)-based (which is multimodal), it may still be difficult to tease out the specific effects elicited by nutritional interventions.
The use of preoperative parenteral nutritional support (PNS) is less well studied than ONS, with most studies tending to look at PNS in the immediate postoperative in-hospital period [16,17 && ]. This may be due to the enhanced logistical burden associated with its management, as well the higher risk profile associated with PNS such as line infections and displacement. Huang et al., found that although the postsurgical complication rate did not improve after giving PNS to 204 sarcopenic patients undergoing radical gastrectomy (although notably hospital costs did), it did reduce the rate of intra-abdominal infections (PNS vs. control, 5.4% vs. 1.2%, P ¼ 0.032) [18]. However, given the increased financial costs associated with PNS as well as a lack of overwhelming evidence for its superiority compared to ONS, it is often used in select cases only.

NUTRITION AS PART OF MULTIMODAL PREHABILITATION
Time from cancer diagnosis to treatment is understandably expeditious to minimize disease progression. For example, in the UK, the National Cancer Action Team stipulate that first treatment must take place within 31 days of decision to treat [19], and as such any preoperative intervention must be effective within this time window. Considering this time constraint, much research has focused on multimodal prehabilitation, commonly including a nutritional component, with a view to implementing as much positive change in a short as time as possible. However, this approach has led to a wide variety of interventions, outcome measures and, on a global level, uncertainty as to the most promising forms of prehabilitation. Further, little insight into the underpinning mechanisms of adaptation in response to these interventions has been garnered to date.
Even when considering just the nutritional components of these interventions, there remains a vast gulf in the degree to which patients are prehabilitated, with many studies offering only advice [21][22][23]29,34,35] whilst others provide routine supplementation [1,25,[30][31][32][33]. Beyond this, Bojesen et al. [36], although arguably not undertaking prehabilitation in its purest sense, offered nutritional screening alone, leaving management of the screening results up to the clinical care team. This study reported an absolute risk reduction in a complicated postoperative course by over 10%. Conversely, on the other end of the spectrum, Lopes et al. [28] took complete control of patient's dietary intake and supplied all nutritional intake to participants. This led to improvements in functional outcomes such as handgrip strength and exercise capacity. To further illustrate this point of intervention variance, a comprehensive systematic review of prehabilitation in patients with esophageal cancer included five studies that included nutritional intervention (versus exercise alone). Again, this ranged from nutritional advice only to varying amounts of differing supplementation (prescribed protein supplementation and direct supplementation with leucine metabolite b-hydroxy-b-methylbutyrate (HMB))[2 terms of improved physical performance, nutritional state and quality of life, clearly this widely varying research base acts as a barrier to implementation of a universal prehabilitation nutritional intervention. This concern, even in homogeneous groups of cancers, is an opinion eloquently summarized by Heil et al. [37 & ], who concluded that conflicting evidence and complex logistical issues were perceived as significant barriers to implementing prehabilitation in colorectal cancer surgery.
Another consideration regarding intervention heterogeneity is group selection. Naturally, prehabilitation is undertaken in diseased cohorts, but as outlined earlier in this article, many studies focus specifically on high(er)-risk patients [23,31,32,36] or patients with more advanced cancers [24,25]. Results in these groups are promising, and concentrating health resources in specific groups of patients may lead to improved outcomes on both an individual and systematic level. However, it may be questioned if this research focus limits the knowledge base around patients who are at lower risk of poor outcomes. Healthier patients and those with less advanced cancers are arguably more likely to return to their precancer status after the insult of cancer and its treatment, so perhaps optimizing these patients prior to surgical intervention would not reduce mortality and significant morbidity but may well lead to a faster return to 'normality' and relatively increased quality-of-life.
Despite this proposition, the concept of high-risk individuals being most responsive to nutritional screening, assessment and/or prehabilitation is well illustrated by Bojesen et al. [36], who assessed patients for anemia, low functional capacity and nutritional status. Postassessment and based only on the assumption of action taken on these results (i.e. referral for nutritional counseling and supplementation), patients could expect an absolute risk reduction of a complicated postoperative course of almost 11%, suggesting that risk-screening alone could improve postoperative outcomes. It may however also be that the nutritional status of patients with esophageal cancer (as studied by Bojesen et al.) is considerably worse than patients with colorectal cancer for instance, due to difficulties in, for example, swallowing solid foods, and that nutritional prehabilitation that addresses this (i.e., ONS) is more effective in those most affected before intervention [21,38].
Inclusion of some outcomes, particularly clinical, may be explained by availability bias; for example, mortality is rarely, if at all, significantly impacted yet is easy to measure [1,2 && ,20,29,38,39,41] However, the inclusion of such diverse outcomes is concerning, especially given the predominant lack of multivariate analysis and correction for multiple comparisons, not to mention the lack of a clear clinical impact of many of the selected measures. This effect is further confounded when adjusting for the multiple and divergent time-points at which these outcomes are measured [20,23,31,42].

CONCLUSION
In summary, recent studies investigating both nutritional only and multimodal prehabilitation for cancer surgery appear as a mosaic of interventions and outcomes which serves as a clear limitation to clinical translation. This is reflected in the American Society of Clinical Oncology (ACSO) guidelines which recommends exercise during cancer treatment, but suggests more research is required for nutritional interventions [2 && ]. However, stepping back from the minutia of individual studies reveals a somewhat clearer picture. Multimodal prehabilitation consistently improves LOS [1,25,32,35,39] and QoL [2

&&
,32], and reduces both complication burden and healthcare associated costs [1,23,25,36]. Importantly given the patient groups in focus, this may lead to an earlier time to adjuvant chemotherapy and/or return to everyday living, and more time spent with loved ones.   www.co-clinicalnutrition.com Based on existent literature, future work could further investigate the financial cost of prehabilitation versus the cost of LOS, the use of wearable devices to aid prehabilitation such as suggested by Waller et al. [29], and/or the involvement of partners in a prehabilitation as suggested by Paterson et al. [43]. A final and interesting consideration for future research for nutritional prehabilitation is the interaction between nutrition and exercise during multimodal prehabilitation; specifically, as suggested by Gillis et al. [44], does optimized nutrition allow an individual to gain the most from a given exercise regime? FIGURE 1. Schematic representation of how the heterogeneity of outcomes in studies exploring nutritional prehabilitation for cancer surgery limit data synthesis and clinical translation.